PI(4,5)P2 is a master regulator for Ca2+-triggered vesicle exocytosis

Substantial evidence indicates that phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ] is a plasma membrane phospholipid essential for Ca 2+ -dependent vesicle exocytosis. Ca 2+ -triggered vesicle exocytosis is a well-organized multiple-step membrane process including vesicle docking, priming, and soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent fusion. A subset of vesicles are docked on high concentration plasma membrane PI(4,5)P 2 microdomains that preferentially undergo exocytosis upon Ca 2+ -stimulation in neuroendocrine cells. PI(4,5)P 2 microdomains also mediate plasma membrane SNARE proteins syntaxin-1 and SNAP-25 partitioning and clustering through electrostatic interactions. PI(4,5)P 2 recruits and activates SNARE regulatory proteins such as calcium-dependent activator protein for secretion (CAPS, aka CADPS), mammalian uncoordinated-13 (Munc13), and synaptotagmin-1, which play pivotal roles in the priming and fusion steps of vesicle exocytosis. In this review, we discuss how PI(4,5)P 2 controls each step of vesicle exocytosis through PI(4,5)P 2 -binding effector proteins.